| Hematopoietic cell transplantation (HCT) requires high dose chemotherapy, radiation and immune suppressants to sustain engraftment and to prevent graft versus host disease. Four clinical pharmacology research studies were designed to provide better therapy to hematopoietic cell transplant patients.; Chapter 1 begins with an introduction to the current status of immunosuppression in HCT. Chapter 2 describes tacrolimus pharmacokinetic parameters, identifies their relationships with clinical covariates and develops a model to predict tacrolimus dosing. Using a population pharmacokinetic approach, 1819 tacrolimus concentrations in 122 patients were used to build the model. Covariates associated with a decrease in tacrolimus clearance included bilirubin, serum creatinine and days posttransplant. The model can be used to individualize tacrolimus dosing regimen to maintain concentrations within the therapeutic window.; Chapter 3 describes an exposure-response relationship between mycophenolic acid pharmacokinetics and acute graft versus host disease and engraftment. Intensive pharmacokinetics sampling was performed in 36 patients with a pretransplant single 1 gram dose of mycophenolate mofetil and again posttransplant with one steady-state dose. Unbound mycophenolic acid area-under-the-curve (AUC) less than 300 ng*hr/mL significantly increased the risk of grade II-IV acute graft versus host disease. Trough mycophenolic acid concentrations were not associated with engraftment or acute graft versus host disease.; Chapter 4 describes the development of a limited pharmacokinetic sampling method to estimate mycophenolic acid AUC. Intensive pharmacokinetic sampling was performed at steady state in 73 patients receiving mycophenolate mofetil 1 gram every 12 hours orally or intravenously. Trough concentrations poorly estimated mycophenolic acid AUC. Three (for intravenous) or four (for oral) sampling time points were needed to determine mycophenolic acid AUC precisely and without bias. The limited sampling strategy provides a simpler method to estimate mycophenolic acid AUC in the clinical setting.; Chapter 5 concludes with an in vitro drug metabolism study to predict an in vivo drug-drug interaction between cyclophosphamide and azole antifungals (fluconazole, itraconazole and voriconazole). Based on experiments in human liver microsomes and cloned, expressed CYP2B6 enzymes, all three antifungals produced in vitro inhibition towards cyclophosphamide activation, with itraconazole being the strongest inhibitor. This data will assist in determining timing and selection of antifungals in HCT. |
